Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. Examples of kinases in the protein kinase family include, without limitation, abl1 (v-ab1 Abelson murine leukemia viral oncogene homolog 1), Akt, Alk, bcr-abl1, c-kit, c-Met, c-src, c-fms, CDK1-10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Fyn, Hck, IGF-1R, Jak, KDR, Lck, Lyn, MEK, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellular processes, kinases have emerged as important therapeutic targets.
Epidermal growth factor (EGF) is a widely distributed growth factor that in cancer, can stimulate cancer-cell proliferation, block apoptosis, activate invasion and metastasis, and stimulate angiogenesis (Citri, et al., Nat. Rev. Mol. Cell. Biol. 7:505, 2006; Hynes, et al., Nat. Rev. Cancer 5:341, 2005). The EGF receptor (EGFR or ErbB) is a transmembrane, tyrosine kinase receptor that belongs to a family of four related receptors. The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of this family (Ciardiello, et al., New Eng. J. Med. 358: 1160, 2008) so that EGF and EGFR are natural targets for cancer therapy.
One member of the EGFR family is ErbB2 (also referred to as the neu or HER-2). The ErbB2 gene is often found amplified in breast or ovarian cancer and in glioblastoma. Over expression of ErbB2 has been demonstrated to lead to increased tumorigenicity, tumor invasiveness, increased metastatic potential, and altered sensitivity to hormonal and chemotherapeutic agents in transfection studies in cellular and animal models (Pegram, et al., Oncogene, 15, 537-547, 1997).